Lung-Targeting Lysostaphin Microspheres for Methicillin-Resistant Staphylococcus aureus Pneumonia Treatment and Prevention

Multifunctional antimicrobial strategies are urgently needed to treat methicillin-resistant Staphylococcus aureus (MRSA) caused pneumonia due to its increasing resistance, enhanced virulence, and high pathogenicity. Here, we report that lysostaphin, a bacteriolytic enzyme, encapsulated within poly(lactic-co-glycolic acid) microspheres (LyIR@MS) specially treats planktonic MRSA bacteria, mature biofilms, and related pneumonia. Optimized LyIR@MS with suitable diameters could deliver a sufficient amount of lysostaphin to the lung without a decrease in survival rate after intravenous injection. Furthermore, the degradable properties of the carrier make it safe for targeted release of lysostaphin to eliminate MRSA, repressing the expression of virulence genes and improving the sensitivity of biofilms to host neutrophils. In the MRSA pneumonia mouse model, treatment or prophylaxis with LyIR@MS significantly improved survival rate and relieved inflammatory injury without introducing adverse events. These findings suggest the clinical translational potential of LyIR@MS for the treatment of MRSA-infected lung diseases.